16 different NIH institutes invest more than $200,000,000 in projects studying T cell responses to simian immunodeficiency virus (SIV), tuberculosis, and influenza. The specificity of cellular CD8+ and CD4+ T cell responses are determined by an individual's repertoire of major histocompatibility complex (MHC) class I and class II alleles, respectively. The apparent complexity of macaque MHC genetics has discouraged investigators from fine-mapping epitope- specific T cell responses. Consequently, only a small number of SIV-specific T cell responses have been characterized in depth, while nearly nothing is known about epitope-specific T cell responses against influenza and BCG (the current vaccine for tuberculosis) in macaques. This constrains investigators interested in monitoring or evaluating T cell responses. Tellingly, there have been shortages of animals possessing the few MHC alleles for which SIV-specific T cell responses and reagents (e.g., MHC:peptide tetramers) are available. Our laboratory recently discovered that MHC allele sharing in Indian rhesus macaques is more common than previously realized. More than 99% of Indian rhesus macaques possess at least one of 16 common MHC class I alleles, while 94% have at least one of 9 common MHC class II -DRB alleles. In this project, we will: 1) Sequentially infect Indian rhesus macaques possessing these 25 common MHC alleles with influenza, BCG, and SIV. T cell responses against all three pathogens will be mapped. 2) Fine-map the epitope specificity and determine the MHC restriction of these CD8+ and CD4+ responses. 3) Produce and distribute MHC:peptide tetramers for responses restricted by the 25 common MHC alleles. We will make new tetramers to measure both CD8+ and CD4+ T cell responses against SIV, influenza, and BCG. The T cell epitopes and MHC:peptide tetramers will be a valuable resource for investigators studying cellular immunity to major infectious diseases. Our team's expertise studying cellular immunity and pathogenesis to SIV, influenza, and BCG in macaque monkeys and our experience with MHC:peptide tetramer production and validation uniquely qualifies us to undertake this ambitious project.